Abstract Compared with the medial temporal lobe and other cortical regions, little attention has been paid to the brainstem in Alzheimer's disease (AD) research. Increasing evidence from various neuropathology studies and recently updated Braak staging, however, suggested that the earliest tau pathology may occur in the brainstem nuclei and propagate to trans-entorhinal cortical regions. While tau PET imaging with the AV1451 tracer is emerging as a powerful tool for measuring cortical tau burden, it is limited for studying the brainstem due to low resolution and off-target binding. On the other hand, great advances in connectome imaging techniques have enabled us to study the integrity of brain pathways with unprecedented detail. Using multi-shell diffusion imaging data from the Human Connectome Project (HCP), we have developed novel tools for computing the fiber orientation distributions (FODs) and compartment models. These tools have been successfully applied to reconstruct challenging fiber pathways in the human brain. In this project, we will leverage cutting-edge connectome and tau PET imaging data from two NIH-funded studies and our novel analysis algorithms to build atlases of brainstem connectomes for AD research. Our goal is to develop the enabling techniques that can provide connectivity measures of brainstem to complement cortical tau burdens from PET imaging. With the novel brainstem atlases and associated software tools developed in this project, we will be able to examine the relation of brainstem and cortical atrophy during the disease course of AD. The findings from such experiments will provide in vivo evidence about the Braak staging of tau pathology in the prodromal phase of AD. In addition, the brainstem connectomes will enable the in vivo mapping of the connectivity changes in neurotransmitter-specific pathways and their relation to behavior symptoms in AD patients. Overall there are three specific aims in this project: 1. To develop atlases of brainstem pathways related to AD using connectome imaging data. 2. To examine the relation of connectivity changes in brainstem nuclei and cortical tau pathology in AD. 3. To study the relation of behavioral symptoms and brainstem connectivity in AD. All atlases and software tools developed in this project will be distributed freely to the research community. While we develop these atlases and tools for studying AD, they should also be valuable in research about other neurological disorders where the brainstem plays an important role.